The interferon (IFN) system is an important physiological defense mechanism against virus infections, and apparently has other biological functions. IFN action on cells must begin with an interaction with cellular receptors which must initiate a chain of events leading to the development of the antiviral and other responses. However, little is known about the IFN receptors, and the events initiated by the IFN receptor interaction. We have demonstrated by binding and crosslinking studies with human cells that [unreadable]125[unreadable]I-labeled human IFN-alpha[unreadable]2[unreadable] (cloned in E. coli) binds to a specific macromolecule (Mr = 130,000) which appears to be the receptor for human IFN-alpha (and IFN-beta) or a component (e.g., the IFN-binding subunit) of it. Studies are planned to characterize the IFN-alpha/beta receptor by biochemical analyses: e.g., to determine whether the receptor is a monomeric or a multimeric molecule, and if the latter, its subunit composition; whether the receptor is a glycoprotein, and if so, whether its carbohydrate component is important for the IFN binding or the development of the cellular response; for example, by testing whether the receptors are susceptible to treatment with neuraminidase and glycosidases or inhibitors of protein glycosylation. We will carry out experiments to solubilize the receptor for fractionation and partial purification, and attempt to raise antibodies against it. We will screen human cell lines which have the IFN-alpha/beta receptors but are insensitive to IFN. Study of the lesion in such cell lines may provide important information regarding the IFN mechanism. Experiments will be carried out to explore the events that follow the IFN receptor interaction, for example, to study the internalization and sub-cellular localization of the internalized IFN and IFN-receptor complex in relation to the development of the cellular response, and to test for covalent modifications such as protein phosphorylation and ADP-ribosylation (as in the case of certain hormones and toxins). These studies would reveal the biochemical characteristics of the IFN receptor system, and provide some necessary information pertaining to the early events initiated by the IFN receptor interaction on the cell surface. (HF)